The present invention relates to spiropyran compounds. In particular, the invention provides indolinospiropyran compounds and methods for their manufacture, which compounds are useful as photochromic compounds.
Various classes of photochromic compounds have been synthesized and suggested for use in applications in which reversible color changes or darkening is induced by sunlight. For example, spiro(indolino)naphthopyrans and spiro(indolino)quinopyrans are described in GB Patent 2,174,711. Spiropyrans also are described in Brown, Glenn H. ed., Photochromism (New York, 1971) and Durr, Heinz and Henri Bouas-Laurent eds., Photochromism (Elsevier, 1990).
Spiropyran derivatives may be the best known organic compounds showing photochromism phenomenon, but the structures of reported spiropyrans are considerably limited. Thus, a need exists both for spiropyran compounds allowing further facile modifications as well as methods for the synthesis of diverse spiropyran compounds.
The present invention provides indolinospiropyran compounds, and particularly photochromic indolinospiropyran compounds, as well as methods for synthesizing these compounds. The indolinospiropyran compounds of the invention are substituted on the indole ring with succinimide, which substitution permits ring opening of the succinimide and modulation of the bulk and photochromic properties of the compounds.
In one embodiment, the invention provides a compound comprising, consisting essentially of, and consisting of the formula: 
wherein R1 is C1-C18 alkyl, allyl, phenyl, mono- or disubstituted phenyl, phen(C1-C4)alkyl, or (C1-C4)alkoxycarbonyl (C1-C4)alkyl, R2 and R3 are each independently C1-C4 alkyl, phenyl, mono- or di-substituted phenyl, benzyl, or combined to form a cyclic ring that is cyclohexyl, norbornyl or adamantyl ring, R4 is hydrogen, hydroxy, trichloromethyl, trifluoromethyl, formyl, C1-C4 alkyl, halogen, C1-C4 alkoxy, nitro, cyano, C1-C4 monohaloalkyl, C1-C4 alkoxycarbonyl, or an aromatic sharing the two adjacent carbon atoms with the benzene portion of the pyran ring to form a condensed aromatic ring including, without limitation, naphthyl, phenanthrenyl, and quinolino, x equals 1, 2, or 3 provided that when x=1, R4 may be located on any of the available carbon atoms of the benzene ring of the benzopyran moiety, preferably on the 6, 7, or 8 position and when x=2, each of the R4 may be the same or different and located at the 6 and 8 or 5 and 7 positions, preferably at the 6 and 8 positions. R1 preferably is a C1-C4 alkyl, phenyl, benzyl, allyl, or ethoxycarbonyl ethyl, R2 and R3 preferably are each independently methyl, ethyl, or phenyl and R4 preferably is C1-C4 alkyl, C1-C2 alkoxy, chloro, bromo, iodo, trifluoromethyl, or nitro.
In a preferred embodiment, the invention provides a compound comprising, consisting essentially of, and consisting of the formula: 
wherein R4 is hydrogen, hydroxy, trifluoromethyl, formyl, methyl, ethyl, methoxy, ethoxy, nitro, fluoro, chloro, bromo, or iodo, and x is 1 or 2.
Because the compounds of formulae I and II contain a succinimide portion, the properties of the compounds, such as solubility, sensitivity and the like, of the invention may be manipulated by ring opening of the succinimide using any of a variety of known methods. Suitable such methods are described, for example, in 48(12) Heterocycles, 2677-2691 (1998).
Formulae I and II compounds may be prepared by any convenient known method and preferably are prepared using a solid phase organic synthesis. The use of solid phase synthesis is advantageous in that it provides ease in execution of the reaction, ease in product purification, and convenient handling of polar molecules throughout the synthetic protocol. Additionally, this approach permits use of commercially available starting materials and use of excess reactant to drive the reaction to completion and to surpass the side reactions. Key in the synthesis is the use of a polymer-supported indoline of the formula: 
wherein R1, R2, and R3 are the same as for formula (I). The solid support may be selected from any of a variety of hydroxy resins. Suitable hydroxy resins include, without limitation, hydroxymethyl polystyrene resin, Wang resin (also known as 4-hydroxymethyl phenoxy resin or xe2x80x9cHMP resinxe2x80x9d), HMPA-PEGA resin (or 4-hydroxymethylphenoxyacetic acid and bisacrylamidoprop-1-yl polyethyleneglycol), HMPB-BHA resin (or 4-hydroxy-3-methoxyphenoxybutyric acid benzhydrylamine), HMPB-MBHA resin (4-hydroxymethyl-3-methoxyphenoxybutyric acid-methylbenzhydrylamine), and combinations thereof The theoretical loading of the resin may be either low (e.g., less than about 0.1 mmole/g) or high (e.g., greater than about 0.4 mmole/g), but for production of greater quantities of product, preferably is high, more preferably about 0.4 to about 1.5 mmole/g. Either of about 100-200 mesh or about 200-400 mesh resin may be used. Preferred resins are an about 100-200 mesh high loading hydroxymethyl polystyrene or a Wang resin.
The solid support used will depend upon the reactants selected, the solvent used, and the product desired. The resin preferably has types and quantities of functional groups that permit efficient attachment of the reactants as well as efficient release of the product. Additionally, the resin must be swellable in the solvent used. The amount of resin used will depend on the amount of reactants used and the reaction scale desired. Generally, about 1 mg to about 100 g of resin may be used.
Formula III compounds, may be prepared by either of two reaction schemes using an aminoindoline compound of the following formula: 
wherein R1, R2, and R3 are as defined for formula I.
The reaction schemes for the preparation of the formula III compound using the aminoindolino compounds are as follows: 
In Method A, an aminoindoline compound of formula IV is treated with succinic anhydride under conditions suitable to form succinamic acid. More specifically, the reaction is carried out at a temperature of about 0 to about 60xc2x0 C., preferably about room temperature, under an inert atmosphere including, without limitation, argon or nitrogen, for about 3 to 24 hours. The amount of reactants used will depend on the amount of product desired and typically will be about 1 mg to about 100 g, preferably about 100 mg to about 10 g. A hydroxy resin along with diisopropyl carbodiimide (xe2x80x9cDICxe2x80x9d) and dimethylamino pyridine (xe2x80x9cDMAPxe2x80x9d) then are added to the mixture to form a suspension bead. This suspension of bead is shaken under conditions suitable to carry out a coupling reaction. Suitable conditions for the reaction are a temperature of about 0 to about 60xc2x0 C., preferably about room temperature, about 14 to 24 hours under an inert atmosphere. Progress of the coupling reaction may be monitored by any convenient means including, without limitation, FT-IR or single bead FT-IR. Typically, the reaction forming the indoline loaded resin is complete after 24 hours at room temperature.
In Method B, hydroxy resin is shaken with an excess of succinic anhydride under conditions suitable to carry out a coupling reaction. Suitable conditions for the reaction are a temperature of about 60 to 120xc2x0 C., preferably about 70 to about 100xc2x0 C., for about 10 to about 60 hours, preferably about 24 to about 48 hours. The progress of the reaction may be monitored by any convenient means and, generally, will be complete after 48 hours of refluxing. After completion of the reaction, excess succinic anhydride is washed away and the resin, now coupled with the succinic acid, is treated with an aminoindoline of formula IV along with 1-hydroxy benzotriazole (xe2x80x9cHOBTxe2x80x9d) and DIC. Conditions suitable for the treatment are a temperature of about 0 to 60xc2x0 C., preferably room temperature, and an inert atmosphere.
In either method, loading typically is over about 95 percent. Any convenient method for testing loading may be used including, without limitation, as disclosed in 63(3) J. Org. Chem., 708-718 (1998). Hexamethyldisiloxane (xe2x80x9cHMDSOxe2x80x9d) may be used as an internal standard for purposes of 1HNMR testing.
The aminoindoline compounds of formula IV may be prepared by reduction of nitroindoline derivatives of the formula: 
wherein R1, R2, and R3 are as for formula I. Suitable nitroindoline derivatives for formula V may be prepared by nitration of indoline derivatives as described in 101(8) Bull. Soc. Chim. Bdg., 719-739 (1992). The indoline derivatives may be nitrated by nitric acid in cold sulfuric acid below 10xc2x0 C., preferably below 7xc2x0 C., over about 10 hours.
In solid phase synthesis of the indolinospiropyran compounds of the invention, a resin loaded with indoline, generally about 100 mg to about 100 g, preferably about 100 mg to about 10 g, as in formula III may be split and treated with any of a variety of salicylaldehyde derivatives under conditions suitable to form the desired indolinospiropyran compound. Suitable conditions for carrying out the synthesis are a temperature of about 50 to 120xc2x0 C. under an inert atmosphere for a time of about 14 to about 11 days, preferably about 14 hours to about 3 days. Suitable salicylaldehyde derivatives are of the formula: 
wherein R4 and x are as for formula I.
The solid phase synthesis proceeds as follows: 
The synthesis is carried out in any suitable solvent, preferably in dioxane, dimethylformamide (xe2x80x9cDMFxe2x80x9d), N-methylprrolidone (xe2x80x9cNMPxe2x80x9d), tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), or combinations thereof. Release of the formula I compound from the solid support may be carried out in any convenient manner such as by a base-catalyzed process using any suitable base including, without limitation, piperidine, DBU, sodium methoxide, potassium tert-butyloxide. In general, about 3 to about 4 equivalents of salicylaldehyde derivative is used to react with about 1.1 to about 10 equivalents, preferably about 2 to about 5, more preferably about 3 to about 4 equivalents of resin loaded with indoline.
The compounds of the invention are useful in any of the wide variety of applications, such as ophthalmic lenses, windshields, windows, and the like in which photochromism is useful. More specifically, an effective amount of the compounds of the invention are incorporated into or coated onto an ophthalmic lens, windshield, window, or like article. The article into which the compound is incorporated or onto which it is coated will darken with exposure to ultra-violet light and revert to its original color or colorless condition in when not exposed to UV light at ambient temperatures. An effective amount of the compound is an amount of about 10xe2x88x925 to about 10xe2x88x922 mol/l, preferably about 10xe2x88x925 to about 10xe2x88x923 mol/l. Methods for incorporating into or coating such articles with photochromic compounds such as those of the invention are well know in the art.